Controlled release formulation

ABSTRACT

A controlled release preparation for oral administration contains tramadol, or a pharmaceutically acceptable salt thereof, as active ingredient.

BACKGROUND OF THE INVENTION

The present invention relates to a controlled release preparation fororal administration, to processes for its preparation and to its medicaluse. In particular, the invention relates to a controlled releasepreparation comprising tramadol or a pharmaceutically acceptable saltthereof.

Tramadol, which has the chemical name(±)-trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, isan orally active opioid analgesic. Conventional release preparations inthe form of capsules, drops and suppositories containing tramadol, ormore particularly its hydrochloride salt, have been commerciallyavailable for many years for use in the treatment of moderate to severepain. Such preparations, however, do not provide a controlled release ofthe tramadol. Moreover, despite tramadol's long-standing use, controlledrelease preparations for oral administration containing tramadol asactive ingredient have not even previously been described in theliterature.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an oral controlledrelease tramadol preparation suitable for at least twelve-hourly (e.g.up to twenty-four hourly) administration for the treatment of pain.

The present invention therefore provides a controlled releasepreparation comprising tramadol or a pharmaceutically acceptable saltthereof for oral administration.

Suitable pharmaceutically acceptable salts of tramadol for use accordingto the present invention are those conventionally known in the art suchas pharmaceutically acceptable acid addition salts. The hydrochloridesalt is particularly preferred.

A controlled release preparation according to the present invention isone that achieves slow release of a drug over an extended period oftime, thereby extending the duration of drug action over that achievedby conventional delivery. Preferably such a preparation maintains a drugconcentration in the blood within the therapeutic range for 12 hours ormore.

The present inventors have found that in order to allow for controlledrelease tramadol over at least a twelve hour period following oraladministration, the in vitro release rate preferably corresponds to thefollowing % rate of tramadol released:

                  TABLE 1                                                         ______________________________________                                        TIME (H)     % RELEASED                                                       ______________________________________                                         1           0-50                                                              2           0-75                                                              4           3-95                                                              8           10-100                                                           12           20-100                                                           16           30-100                                                           24           50-100                                                           36           >80                                                              ______________________________________                                    

Another preferred preparation especially suited for twice-a-day dosinghas an in vitro release rate corresponding to the following % rate oftramadol released:

                  TABLE 2                                                         ______________________________________                                        TIME (H)     % RELEASED                                                       ______________________________________                                        1            20-50                                                            2            40-75                                                            4            60-95                                                            8             80-100                                                          12            90-100                                                          ______________________________________                                    

Yet another preferred preparation particularly suited for once-a-daydosing has an in-vitro release rate corresponding to the following %rate of tramadol released:

                  TABLE 3                                                         ______________________________________                                        TIME (H)     % RELEASED                                                       ______________________________________                                        1            0-50                                                             2            0-75                                                             4            10-95                                                            8            35-100                                                           12           55-100                                                           16           70-100                                                           24           >90                                                              ______________________________________                                    

A still farther preferred preparation in accordance with the inventionalso particularly suited for once-a-day dosing has an in vitro releaserate corresponding to the following % rate of tramadol released.

                  TABLE 4                                                         ______________________________________                                        TIME (H)     % RELEASED                                                       ______________________________________                                         1           0-30                                                              2           0-40                                                              4           3-55                                                              8           10-65                                                            12           20-75                                                            16           30-88                                                            24           50-100                                                           36           >80                                                              ______________________________________                                    

More preferably a preparation for once-a-day dosing has an in vitrorelease rate substantially as follows;

    ______________________________________                                        TIME (H)   % TRAMADOL RELEASED                                                ______________________________________                                        1          15-25                                                              2          25-35                                                              4          30-45                                                              8          40-60                                                              12         55-70                                                              16         60-75                                                              ______________________________________                                    

Another preferred dissolution rate in vitro upon release of thecontrolled release preparation for administration twice daily accordingto the invention, is between 5 and 50% (by weight) tramadol releasedafter 1 hour, between 10 and 75% (by weight) tramadol released after 2hours, between 20 and 95% (by weight) tramadol released after 4 hours,between 40 and 100% (by weight) tramadol released after 8 hours, morethan 50% (by weight) tramadol released after 12 hours, more than 70% (byweight) released after 18 hours and more than 80% (by weight) tramadolreleased after 24 hours.

Furthermore, it is preferred in the case of a controlled releasepreparation for administration twice daily that after 8 hours followingoral administration between 70 and 95% (by weight) tramadol is absorbedin vivo, between 77 and 97% (by weight) tramadol is absorbed after 10hours and between 80 and 100% (by weight) tramadol is absorbed after 12hours.

A formulation in accordance with the invention suitable for twice-a-daydosing may have a tmax of 1.5 to 8 hours, preferably 2 to 7 hours, and aW₅₀ value in the range 7 to 16 hours.

A formulation in accordance with the invention suitable for once-a-daydosing may have a tmax in the range of 3 to 6 hours, preferrably 4 to 5hours and a W₅₀ value in the range of 10 to 33 hours.

The W₅₀ parameter defines the width of the plasma profile at 50% Cmax,i.e. the duration over which the plasma concentrations are equal to orgreater than 50% of the peak concentration. The parameter is determinedby linear interpolation of the observed data and represents thedifference in time between the first (or only) upslope crossing and thelast (or only) downslope crossing in the plasma profile.

The in vitro release rates mentioned herein are, except where otherwisespecified, those obtained by measurement using the Ph. Eur. PaddleMethod at 100 rpm in 900 ml 0.1N hydrochloric acid at 37° C. and usingUV detection at 270 nm.

The in vivo absorption rate is determined from measurement of plasmaconcentration against time using the deconvolution technique. Aconventional release tramadol drop preparation (Tramal (trade mark),Grunenthal) was used as the weighting-function and the elimination halflife of tramadol was taken as 7.8 hours.

The controlled release preparation according to the invention preferablycontains an analgesically effective amount of tramadol or apharmaceutically acceptable salt thereof, conveniently in the range offrom 50 to 800 mg, especially 100, 200, 300, 400 to 600 mg (calculatedas tramadol hydrochloride) per dosage unit.

The controlled release preparation according to the invention may bepresented, for example, as granules, spheroids, pellets,multiparticulates, capsules, tablets, sachets, controlled releasesuspensions, or in any other suitable dosage form incorporating suchgranules, spheroids, pellets or multiparticulates.

The active ingredient in the preparation according to the invention maysuitably be incorporated in a matrix. This may be any matrix thataffords controlled release tramadol over at least a twelve hour periodand preferably that affords in-vitro dissolution rates and in vivoabsorption rates of tramadol within the ranges specified above.Preferably the matrix is a controlled release matrix. Alternatively,normal release matrices having a coating which provides for controlledrelease of the active ingredient may be used.

Suitable materials for inclusion in a controlled release matrix include

(a) Hydrophillic or hydrophobic polymers, such as gums, celluloseethers, acrylic resins and protein derived materials. Of these polymers,the cellulose ethers, especially alkylcelluloses are preferred. Thepreparation may conveniently contain between 1% and 80% (by weight) ofone or more hydrophillic or hydrophobic polymers.

(b) Digestible, long chain (C₈ -C₅₀, especially C₁₂ -C₄₀), substitutedor unsubstituted hydrocarbons, such as fatty acids, fatty alcohols,glyceryl esters of fatty acids, mineral and vegetable oils and waxes.Hydrocarbons having a melting point of between 25° and 90° C. arepreferred. Of these long chain hydrocarbon materials, fatty (aliphatic)alcohols are preferred. The preparation may conveniently contain up to60% (by weight) of at least one digestible, long chain hydrocarbon.

(c) Polyalkylene glycols. The preparation may suitably contain up to 60%(by weight) of one or more polyalkylene glycols.

One particularly suitable controlled release matrix comprises one ormore alkylcelluloses and one or more C₁₂ -C₃₆ aliphatic alcohols. Thealkylcellulose is preferably C₁ -C₆ alkyl cellulose, especially ethylcellulose. The controlled release preparation according to the inventionpreferably contains from 1 to 20% (by weight), especially from 2 to 15%(by weight) of one or more alkylcelluloses.

The aliphatic alcohol may conveniently be lauryl alcohol, myristylalcohol or stearyl alcohol but is preferably cetyl alcohol or morepreferably cetostearyl alcohol. The controlled release preparationsuitably contains from 5 to 30% (by weight) of aliphatic alcohol,especially from 10 to 25% (by weight) of aliphatic alcohol.

Optionally the controlled release matrix may also contain otherpharmaceutically acceptable ingredients which are conventional in thepharmaceutical art such as diluents, lubricants, binders, granulatingaids, colorants, flavorants, surfactants, pH adjusters, anti-adherentsand gildants, e.g. dibutyl sebacate, ammonium hydroxide, oleic acid andcolloidal silica.

The controlled release preparation according to the invention mayconveniently be film coated using any film coating material conventionalin the pharmaceutical art. Preferably an aqueous film coating is used.

Alternatively, the controlled release preparation according to theinvention may comprise a normal release matrix having a controlledrelease coating. Preferably the preparation comprises film coatedspheroids containing the active ingredient and a spheronising agent.

The spheronising agent may be any suitable pharmaceutically acceptablematerial which may be spheronised together with the active ingredient toform spheroids. A preferred spheronising agent is microcrystallinecellulose. The microcrystalline cellulose used may suitably be, forexample, Avicel PH 101 or Avicel PH 102 (Trade Marks, FMC Corporation).

Optionally the spheroids may contain other pharmaceutically acceptableingredients conventional in the pharmaceutical art such as binders,bulking agents and colorants. Suitable binders include water solublepolymers, water soluble hydroxyalkyl celluloses such ashydroxypropylcellulose or water insoluble polymers (which may alsocontribute controlled release properties) such as acrylic polymers orcopolymers for example ethylcellulose. Suitable bulking agents includelactose.

The spheroids are coated with a material which permits release of theactive ingredient at a controlled rate in an aqueous medium. Suitablecontrolled release coating materials include water insoluble waxes andpolymers such as polymethacrylates (for example Eudragit polymers, TradeMark) or water insoluble celluloses, particularly ethylcellulose.Optionally, water soluble polymers such as polyvinylpyrrolidone or watersoluble celluloses such as hydroxypropylmethylcellulose orhydroxypropylcellulose may be included. Optionally other water solubleagents such as polysorbate 80 may be added.

Alternatively the drug may be coated onto inert non-pareil beads and thedrug loaded beads coated with a material which permits control of therelease of the active ingredient into the aqueous medium.

In a further aspect the present invention provides a process forpreparing a controlled release preparation according to the presentinvention comprising incorporating tramadol or a pharmaceuticallyacceptable salt thereof in a controlled release matrix:

(a) granulating a mixture comprising tramadol or a pharmaceuticallyacceptable salt thereof and one or more alkylcelluloses,

(b) mixing the alkylcellulose containing granules with one or moreC₁₂₋₃₆ aliphatic alcohols; and optionally

(c) shaping and compressing the granules, and film coating, if desired;or

(d) granulating a mixture comprising tramadol or a pharmaceuticallyacceptable salt thereof, lactose and one or more alkylcelluloses withone or more C₁₂₋₃₆ aliphatic alcohol; and, optionally,

(e) shaping and compressing the granules, and film coating, if desired.

The controlled release preparation according to the invention may alsobe prepared in the form of film coated spheroids by

(a) granulating the mixture comprising tramadol or a pharmaceuticallyacceptable salt thereof and a spheronising agent;

(b) extruding the granulated mixture to give an extrudate;

(c) spheronising the extrudate until spheroids are formed; and

(d) coating the spheroids with a film coat.

One preferred form of unit dose form in accordance with the inventioncomprises a capsule filled with controlled release particles essentiallycomprising the active ingredient, a hydrophobic fusible carrier ordiluent and optionally a hydrophillic release modifier. In particular,the controlled release particles are preferably prepared by a processwhich comprises forming a mixture of dry active ingredient and fusiblerelease control materials followed by mechanically working the mixturein a high speed mixer with an energy input sufficient to melt or softenthe fusible material whereby it forms particles with the activeingredient. The resultant particles, after cooling, are suitably sievedto give particles having a size range from 0.1 to 3.0 min, preferably0.25 to 2.0 mm. An example according to the invention is described belowwhich is suitable for the commercial production of dosage units.

When using such a processing technique it has been found that, in ordermost readily to achieve the desired release characteristics (both invivo and in vitro as discussed above) the composition to be processedshould comprises two essential ingredients namely:

(a) tramadol or salt thereof; and

(b) hydrophobic fusible carrier or diluent; optionally together with

(c) a release control component comprising a water-soluble fusiblematerial or a particulate soluble or insoluble organic or inorganicmaterial.

We have found that the total amount of tramadol or pharmaceuticallyacceptable salt thereof in the composition may vary within wide limits,for example from 10 to 90% by weight thereof.

The hydrophobic fusible component (b) should be a hydrophobic materialsuch as a natural or synthetic wax or oil, for example hydrogenatedvegetable oil, hydrogenated castor oil, microcrystalline wax, Beeswax,Carnauba wax or glyceryl monostearate, and suitably has a melting pointof from 35° to 140° C., preferably 45° to 110° C.

The release modifying component (c), when a water soluble fusiblematerial, is conveniently a polyethylene glycol and, when a particulatematerial, is conveniently a pharmaceutically acceptable material such asdicalcium phosphate or lactose.

Another preferred process for the manufacture of a formulation inaccordance with the invention comprises

(a) mechanically working in a high-speed mixer, a mixture of tramadol ora pharmaceutically acceptable salt in particulate form and aparticulate, hydrophobic fusible carrier or diluent having a meltingpoint from 35° to 140° C. and optionally a release control componentcomprising a water soluble fusible material, or a particulate soluble orinsoluble organic or inorganic material at a speed and energy inputwhich allows the carrier or diluent to melt or soften, whereby it formsagglomerates,

(b) breaking down the larger agglomerates to give controlled releaseseeds; and

(c) continuing mechanically working with optionally a further additionof low percentage of the carrier or diluent.

(d) optionally repeating steps (c) and possibly (b) one or more times.

This process is capable of giving a high yield (over 80%) of particlesin a desired size range, with a desired uniformity of release rate oftramadol or salt thereof.

The resulting particles may be sieved to eliminate any over-orundersized material then formed into the desired dosage units by forexample, encapsulation into hard gelatin capsules containing therequired dose of the active substance or by compression into tablets.

In this method in accordance with the invention preferably all thetramadol or salt thereof is added in step (a) together with a majorportion of the hydrophobic fusible release control material used.Preferably the amount of fusible release control material added in step(a) is between 10% and 90% w/w of the total amount of ingredients addedin the entire manufacturing operation, more preferably between 20% and70% w/w.

Stage (a) of the process may be carried out in conventional high speedmixers with a standard stainless steel interior, e.g. a Collette Vactron75 or equivalent mixer. The mixture is processed until a bed temperatureabout 40° C. or above is achieved and the resulting mixture acquires acohesive granular texture, with particle sizes ranging from about 1-3 mmto fine powder in the case of non-aggregated original material. Suchmaterial, in the case of the embodiments described below, has theappearance of agglomerates which upon cooling below 40° C. havestructural integrity and resistance to crushing between the fingers. Atthis stage the agglomerates are of an irregular size, shape andappearance.

The agglomerates are preferably allowed to cool. The temperature towhich it cools is not critical and a temperature in the range roomtemperature to 37° C. may be conveniently used.

The agglomerates are broken down by any suitable means, which willcomminute oversize agglomerates and produce a mixture of powder andsmall particles preferably with a diameter under 2 mm. It is currentlypreferred to carry out the classification using a Jackson Crockattgranulator using a suitable sized mesh, or a Comil with an appropriatesized screen. We have found that if too small a mesh size is used in theaforementioned apparatus the agglomerates melting under the action ofthe beater or impeller will clog the mesh and prevent further throughputof mixture, thus reducing yield. A mesh size of 12 has been foundadequate.

The classified material is returned to the high speed mixer andprocessing continued. It is believed that this leads to cementation ofthe finer particles into particles of uniform size range.

In one preferred form of the method of the invention processing of theclassified materials is continued, until the hydrophobic fusiblematerials used begin to soften/melt and optionally additionalhydrophobic fusible material is then added. Mixing is continued untilthe mixture has been transformed into particles of the desiredpredetermined size range.

In order to ensure uniform energy input into the ingredients in the highspeed mixer it is preferred to supply at least part of the energy bymeans of microwave energy.

Energy may also be delivered through other means such as by a heatingjacket or via the mixer impeller and chopper blades.

After the particles have been formed they are cooled or allowed to cool,and may then be sieved to remove any over or undersized material.

The resulting particles may be used to prepare dosage units inaccordance with the invention in the form of e.g. tablets or capsules inmanners known per se.

We have also found that particles containing tramadol or a salt thereofproduced by a melt processing as described in application PCT/SE93/00225and the process described and claimed in our prior unpublished UKapplication No. 9324045.5 filed on 23 Nov. 1993 as well as the processdescribed herein are particularly useful for processing into the form oftablets.

We have found that by suitable selection of the materials used informing the particles and in the tabletting and the proportions in whichthey are used, enables a significant degree of control in the ultimatedissolution and release rates of the tramadol or salt thereof from thecompressed tablets.

Usually, to form a tablet in accordance with the invention, particlesprepared as described above will be admixed with tabletting excipientse.g. one or more or the standard excipients such as diluents,lubricants, binding agents, flow aids, disintegrating agents, surfaceactive agents or water soluble polymeric materials.

Suitable diluents are e.g. microcrystalline cellulose, lactose anddicalcium phosphate. Suitable lubricants are e.g. magnesium stearate andsodium stearyl fumarate. Suitable binding agents are e.g. hydroxypropylmethyl cellulose, polyvidone and methyl cellulose.

Suitable disintegrating agents are starch, sodium starch glycolate,crospovidone and croscarmalose sodium. Suitable surface active arePoloxamer 188®, polysorbate 80 and sodium lauryl sulfate. Suitable flowaids are talc colloidal anhydrous silica. Suitable water solublepolymers are PEG with molecular weights in the range 1000 to 6000.

To produce tablets in accordance with the invention, particles producedin accordance with the invention may be mixed or blended with thedesired excipient(s), if any, using conventional procedures, e.g. usinga Y-Cone or bin-blender and the resulting mixture compressed accordingto conventional tabletting procedure using a suitable size tablettingmold. Tablets can be produced using conventional tabletting machines,and in the embodiments described below were produced on standard singlepunch F3 Manesty machine or Kilian RLE15 rotary tablet machine.

Generally speaking we find that even with such a highly water solubleactive agent as tramadol or salt thereof tablets formed by compressionaccording to standard methods give very low release rates of the activeingredient e.g. corresponding to release over a period of greater than24 hours, say more than 36. We have found that the release profile canbe adjusted in a number of ways. For instance a higher loading of thedrug will be associated with increased release rates; the use of largerproportions of the water soluble fusible material in the particles orsurface active agent in the tabletting formulation will also beassociated with a higher release rate of the active ingredient. Bycontrolling the relative amounts of these ingredients it is possible toadjust the release profile of the tramadol or salt thereof.

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is further illustrated in connection with theaccompanying drawings in which:

FIG. 1 is a graphical depiction of the serum levels of tramadolfollowing administration of one tablet according to Example 2 in 12healthy volunteers; and

FIG. 2 is a graphical depiction of the plasma profile resulting fromsingle dose administration of the tablet of Example 8 in comparison tothe administration of a commercial preparation of tramadol drops 100 mgin a trial involving five healthy male volunteers.

EXAMPLE 1

Tablets having the following formulation were prepared:

    ______________________________________                                                             mg/tablet                                                ______________________________________                                        Tramadol Hydrochloride 100                                                    Lactose Ph. Eur.       68.0                                                   Ethylcellulose (Surelease ® 25% solids)                                                          15                                                     Purified Water Ph. Eur.                                                                              13.3*                                                  Cetostearyl Alcohol Ph. Eur.                                                                         42.00                                                  (Dehydag wax 0)                                                               Magnesium Stearate Ph. Eur.                                                                           2.00                                                  Purified Talc Ph. Eur.  3.00                                                                         230.00                                                 ______________________________________                                         *Removed during processing.                                              

Tramadol hydrochloride (100 mg) and lactose (68 mg) were granulated,transferred to a fluid bed granulator and sprayed with ethylcellulose(15 mg) and water. The granules were then dried at 60° C. and passedthrough a 1 mm screen.

To the warmed tramadol containing granules was added molten cetostearylalcohol (42 mg) and the whole was mixed thoroughly. The granules wereallowed to cool and sieved through a 1.6 mm screen. Purified talc andmagnesium stearate were added and mixed with the granules. The granuleswere then compressed into tablets.

The tablets were coated with a film coat having the formulation givenbelow.

    ______________________________________                                                            mg/tablet                                                 ______________________________________                                        Hydropropylmethylcellulose                                                                          0.770                                                   Ph. Eur. 15 cps (Methocel E15)                                                Hydroxypropylmethylcellulose                                                                        3.87                                                    (Ph. Eur. 5 cps (Methocel E5)                                                 Opaspray M-1-7111B (33% solids)                                                                     2.57                                                    Polyethylene glycol 400 USNF                                                                        0.520                                                   Purified Talc Ph. Eur.                                                                              0.270                                                   Purified Water Ph. Eur.                                                                             55.52*                                                  ______________________________________                                         *Remove during processing.                                               

EXAMPLE 2

Tablets having the following formulation were prepared:

    ______________________________________                                                          mg/tablet                                                   ______________________________________                                        Tramadol hydrochloride                                                                            100.0                                                     Lactose Ph. Eur.    58.0                                                      Ethylcellulose USNF 15.0                                                      (Ethocel 45 CP)                                                               Cetostearyl alcohol Ph. Eur.                                                                      52.0                                                      (Dehydag wax O)                                                               Magnesium stearate Ph. Eur.                                                                        2.00                                                     Purified talc Ph. Eur.                                                                             3.00                                                     ______________________________________                                    

A mixture of tramadol hydrochloride (100 mg), lactose (58 mg) andethylcellulose (15 mg) was granulated while adding molten cetostearylalcohol (52 mg) and the whole was mixed thoroughly. The granules wereallowed to cool and sieved through a 1.6 mm screen. Purified talc andmagnesium stearate were added and mixed with the granules. The granuleswere then compressed into tablets which were coated with a film coathaving the formulation given in Example 1.

EXAMPLE 3

Film coated tablets were produced following the procedure described inExample 2 and having the following formulation:

    ______________________________________                                                           mg/tablet                                                  ______________________________________                                        Tramadol hydrochloride                                                                             100.00                                                   Lactose Ph. Eur.     70.50                                                    Hydroxyethylcellulose Ph. Eur.                                                                     12.50                                                    Cetostearyl alcohol Ph. Eur.                                                                       42.00                                                    Magnesium stearate Ph. Eur.                                                                        2.00                                                     Purified talc Ph. Eur.                                                                             3.00                                                     ______________________________________                                    

In vitro dissolution studies

In vitro dissolution studies were conducted on tablets prepared asdescribed above. Results are given in Table 1.

                  TABLE 1                                                         ______________________________________                                        WT % TRAMADOL RELEASED                                                        Time (h) Example 1    Example 2*                                                                              Example 3                                     ______________________________________                                        1        39           35        43                                            2        52           47        60                                            4        67           62        84                                            8        82           78        97                                            12       90           86        --                                            ______________________________________                                         *Measured on tablet core                                                 

In a trial involving 12 healthy volunteers the serum levels of tramadolfollowing administration of one tablet according to Example 2 was foundto be as illustrated in FIG. 1.

EXAMPLE 4 and 5

Particles having the formulations given in Table II below, were preparedby the steps of:

i. Placing the ingredients (a) and (c) (total batch weight 0.7 kg) inthe bowl of a 10 liter capacity Collette Gral Mixer (or equivalent)equipped with variable speed mixing and granulating blades;

ii. Mixing the ingredients at about 150-1000 rpm whilst applying heatuntil the contents of the bowl are agglomerated.

iii. Classifying the agglomerated material by passage through a Comiland/or Jackson Crockatt to obtain controlled release seeds.

iv. Warming and mixing the classified material in the bowl of a 10 literCollette Gral, until uniform multiparticulates of the desiredpre-determined size range are formed in yield of greater than 80%. Thistakes approximately 5 minutes.

V. Discharging the multiparticulates from the mixer and sieving them toseparate out the multiparticulates collected between 0.5 and 2 mmaperture sieves.

                  TABLE II                                                        ______________________________________                                        Example                  4     5                                              ______________________________________                                        (a) Tramadol HCl (Wt %)  50    75                                             (b) Hydrogenated Vegetable Oil (Wt %)                                                                  50    25                                             ______________________________________                                    

EXAMPLE 6

Samples of the particles from Example 4 were blended with magnesiumstearate and purified talc using a Y-Cone or bin-blender. The blendedmixture was then compressed using either (1) 14×6 mm, (2) 16×7 mm or (3)18.6×7.5 mm capsule shaped tooling on a single punch F3 Manestytabletting machine to give tablets giving 200, 300 and 400 mg oftramadol HCl. The ingredients per dosage unit amounted to the following:

                  TABLE III                                                       ______________________________________                                        TABLET          MG/TABLET                                                     INGREDIENT      1         2        3                                          ______________________________________                                        Tramadol Hcl    200       300      400                                        Hydrogenated Vegetable Oil                                                                    200       300      400                                        Sub Total       400       600      800                                        Purified Talc      12.63     18.95    25.26                                   Magnesium Stearate                                                                               8.42      12.63    16.84                                   ______________________________________                                    

The tablets were assessed by the dissolution using Ph. Eur. PaddleMethod 100 rpm, 0.1N HCl.

To assess the non-compressed particles the Ph Eur. Paddle was replacedby a modified Ph Eur. Basket.

The results are shown in Table IV below;

                  TABLE IV                                                        ______________________________________                                        HOURS AFTER Particles                                                                              Tablet 1  Tablet 2                                                                             Tablet 3                                START OF TEST                                                                             % TRAMADOL HCl RELEASED                                           ______________________________________                                        1           54       16        15     15                                      2           68       23        20     21                                      3           76       28        25     25                                      4           82       32        28     28                                      6           89       40        35     35                                      8           93       46        41     40                                      10          96       50        45     45                                      12          98       55        49     49                                      16          100      63        57     56                                      20          NR       70        63     NR                                      ______________________________________                                    

These results confirm the effectiveness of the tabletting in reducingthe release rate.

EXAMPLE 7

Samples of the particles from Example 5 were then tabletted using aprocedure similar to Example 3 and the ingredients per unit dosageamounted to:

                  TABLE V                                                         ______________________________________                                        TABLET          MG/TABLET                                                     INGREDIENT      4         5        6                                          ______________________________________                                        Tramadol Hcl    200       300      400                                        Hydrogenated Vegetable Oil                                                                    66.7      100      133                                        Sub Total       266.7     400      533                                        Purified Talc   7.63         11.44    15.25                                   Magnesium Stearate                                                                            5.16         7.63     10.17                                   ______________________________________                                    

The tablets and samples of non-compressed multiparticulates (each samplecontaining 400 mg of tramadol hydrochloride) were assessed by thedissolution method also described above. The results are shown in TableVI below;

                  TABLE VI                                                        ______________________________________                                        HOURS AFTER Particles                                                                              Tablet 4  Tablet 5                                                                             Tablet 6                                START OF TEST                                                                             % TRAMADOL HCl RELEASED                                           ______________________________________                                        1            77      43        40     42                                      2            92      64        55     56                                      3            98      75        65     66                                      4           100      83        72     73                                      6           102      94        83     84                                      8           102      100       91     91                                      10          102      NR        96     97                                      ______________________________________                                    

These results show that by increasing the loading of the highly watersoluble tramadol hydrochloride (75% w/w in this example compared with50% w/w in Example 6) a significantly faster release rate of the activeingredient can be achieved.

EXAMPLE 8

Example 4 was repeated but with the following formulation:

    ______________________________________                                        Tramadol HCl         200 mg/tablet                                            Hydrogenated Vegetable Oil                                                                         163.0 mg/tablet                                          ______________________________________                                    

The resulting multiparticulates were blended as described in Example 6with the following;

    ______________________________________                                        Purified Talc       11.5 mg/tablet                                            Magnesium Stearate  7.66 mg/tablet                                            ______________________________________                                    

The blend was then compressed as described in Example 6 but using 15mm×6.5 mm normal concave capsule shaped plain/plain punches.

The resulting tablets were then assessed by the dissolution methoddescribed above. The results are shown in Table V.

    ______________________________________                                        HOURS AFTER START                                                                              % TRAMADOL HCl                                               OF TEST          RELEASED                                                     ______________________________________                                        1                20                                                           2                27                                                           3                32                                                           4                37                                                           6                44                                                           8                50                                                           10               55                                                           12               60                                                           16               67                                                           20               73                                                           24               77                                                           ______________________________________                                    

In a trial involving five healthy male volunteers the plasma profileresulting from single dose administrations of the above tablet are shownin FIG. 2 in comparison to the administration of a commercialpreparation of Tramadol drops 100 mg.

The examples provided above are not meant to be exclusive. Many othervariation of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims.

What is claimed is:
 1. A controlled release oral pharmaceuticalpreparation suitable for dosing every 24 hours containing from about 50mg to about 800 mg of tramadol or a pharmaceutically acceptable saltthereof, calculated as hydrochloride salt, in a controlled releasematrix, the matrix comprising from about 1 to about 80% w/w of one ormore hydrophilic or hydrophobic polymers, and having a dissolution ratein vitro when measured using the Ph. Eur. Paddle Method at 100 rpm in900 ml 0.1N hydrochloric acid at 37° C. and using UV detection at 270nm, from about 0 to about 50% tramadol released after 1 hour; from about0 to about 75% tramadol released after 2 hours; from about 3 to about95% tramadol released after 4 hours; from about 10 to about 100% after 8hours; from about 20 to about 100% tramadol released after 12 hours;from about 30 to about 100% tramadol released after 16 hours; from about50 to about 100% tramadol released after 24 hours; and greater than 80%tramadol released after 36 hours, by weight.
 2. A controlled releasepreparation as claimed in claim 1, having an in-vitro dissolution rate(measured by the Ph. Euro Paddle method at 100 rpm in 900 ml 0.1Nhydrochloric acid at 37° C. and using UV detection at 270 mm) as setforth below:

    ______________________________________                                        TIME (H)     % RELEASED                                                       ______________________________________                                        1            20-50                                                            2            40-75                                                            4            60-95                                                            8             80-100                                                          12            90-100                                                          ______________________________________                                    


3. A controlled release preparation as claimed in claim 1, having anin-vitro dissolution rate (measured by the Ph. Eur. Paddle method at 100rpm in 900 ml 0.1N hydrochloric acid at 37° C. and using UV detection at270 mm) as set forth below:

    ______________________________________                                        TIME (H)     % RELEASED                                                       ______________________________________                                        1            0-50                                                             2            0-75                                                             4            10-95                                                            8            35-100                                                           12           55-100                                                           16           70-100                                                           24           >90                                                              ______________________________________                                    


4. A controlled release preparation as claimed in claim 1, having anin-vitro dissolution rate (measured by the Ph. Eur. Paddle method at 100rpm in 900 ml 0.1N hydrochloric acid at 37° C. and using UV detection at270 mm) as set forth below:

    ______________________________________                                        TIME (H)     % RELEASED                                                       ______________________________________                                         1           0-30                                                              2           0-40                                                              4           3-55                                                              8           10-65                                                            12           20-75                                                            16           30-88                                                            24           50-100                                                           36           >80                                                              ______________________________________                                    


5. A dosage form according to claim 1, wherein said matrix comprises acellulose ether.
 6. A dosage form according to claim 5, wherein saidmatrix comprises a controlled release matrix comprising at least onealkylcellulose, at least one C₁₂ to C₃₆, aliphatic alcohol and,optionally at least one polyalkylglycol.
 7. A dosage form as claimed inclaim 6, wherein said polyalkylglycol is polyethylene glycol.
 8. Adosage form according to claim 6, wherein said at least one C₁₂ to C₃₆aliphatic alcohol is a C₁₄ to C₂₂ aliphatic alcohol.
 9. A dosage formaccording to claim 6, wherein said alkylcellulose is a C₁ -C₆alkylcellulose.
 10. A dosage form according to claim 6, wherein thedosage form contains from about 1 to about 20% w/w of saidalkylcellulose.
 11. A dosage form according to claim 6, wherein saidaliphatic alcohol is selected from the group consisting of laurylalcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol, cetostearylalcohol, and mixtures thereof.
 12. The dosage form of claim 11, whereinsaid aliphatic alcohol is cetyl alcohol or cetostearyl alcohol.
 13. Adosage form according to claim 6, wherein said dosage form contains fromabout 5 to about 30% w/w of said aliphatic alcohol.
 14. A dosage formaccording to claim 6, wherein said dosage form contains from about 10 toabout 25% w/w of said aliphatic alcohol.
 15. A dosage form according toclaim 1, in the form of film coated spheroids, wherein said spheroidmatrix comprises a spheronizing agent.
 16. A dosage form according toclaim 1, in the form of multi-particulates wherein said matrix comprisesa hydrophobic fusible carrier or diluent having a melting point from 35°to 140° C. and optionally a release control component comprising a watersoluble fusible material, or a particulate soluble or insoluble organicor inorganic material.
 17. A dosage form according to claims 1, whichcomprises a tablet formed by compressing a multiparticulate according toclaim
 16. 18. A dosage form according to claim 5, wherein said celluloseether is an alkylcellulose.
 19. A dosage form according to claim 18,wherein said alkylcellulose is ethylcellulose.
 20. A dosage formaccording to claim 1 which provides a t_(max) from about 3 to about 6hours.
 21. A dosage form according to claim 1 which provides a W₅₀ fromabout 10 to about 33 hours.
 22. A controlled release preparationsuitable for dosing every twelve hours containing from about 50 to about400 mg tramadol or pharaceutically acceptable salt thereof, calculatedas the hydrochloride salt, in a controlled release matrix containingfrom about 1 to about 80% w/w of one or more hydrophilic or hydrophobicpolymers, said preparation exhibiting an in vitro dissolution rate whenmeasured by the Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1Nhydrochloric acid at 37° C. and using UV detection at 270 mm, such thatbetween 5 and 50% (by weight) tramadol is released after 1 hour, between10 and 75% (by weight) tramadol is released after 2 hours, between 20and 95% (by weight) tramadol is released after 4 hours, between 40 and100% (by weight) tramadol is released after 8 hours, more than 50% (byweight) tramadol is released after 12 hours, more than 70% (by weight)tramadol is released after 18 hours and more than 80% (by weight)tramadol is released after 24 hours.
 23. A dosage form according toclaim 22 wherein said controlled release matrix comprises a celluloseether.
 24. A dosage form according to claim 23 wherein said celluloseether is an alkyl cellulose.
 25. A dosage form according to claim 22wherein said controlled release matrix comprises at least one C₁ to C₆,alkyl cellulose.
 26. A dosage form according to claim 25, wherein saidcontrolled release matrix comprises at least one C₁₂ to C₃₆, aliphaticalcohol.
 27. A dosage form according to claim 26, wherein saidcontrolled release matrix further comprises at least one C₁₄ to C₂₂aliphatic alcohol.
 28. A dosage form according to claim 27, wherein saidcontrolled release matrix further comprises at least onepolyalkylglycol.
 29. A dosage form according to claim 28, wherein saidpolyalkylglycol is polyethylene glycol.
 30. A dosage form according toclaim 25, wherein said dosage form contains from about 1 to about 20%w/w of said alkyl cellulose.
 31. A dosage form according to claim 29,wherein said dosage form contains from about 2 to 15% w/w of said alkylcellulose.
 32. A dosage form according to claim 26, wherein saidaliphatic alcohol is selected from the group consisting of laurylalcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol cetostearylalcohol, and mixtures thereof.
 33. A dosage form according to claim 32,wherein said dosage form contains from about 5 to about 30% w/waliphatic alcohol.
 34. A dosage form according to claim 32, wherein saiddosage form contains from about from 10 to 25% w/w aliphatic alcohol.35. A dosage form according to claim 25 in the form of multiparticulatespheroid matrices, wherein said spheroid matrix comprises a spheronizingagent.
 36. A dosage form according to claim 35, wherein saidspheronizing agent comprises microcrystalline cellulose.
 37. A dosageform according to claim 22, in the form of multiparticulates whereinsaid matrix comprises a hydrophobic fusible carrier or diluent having amelting point from 35° to 140° C. and optionally a release controlcomponent comprising a water soluble fusible material, or a particulatesoluble or insoluble organic or inorganic material.
 38. A dosage formaccording to claim 22, which provides a t_(max) from about 1.5 to about8 hours.
 39. A dosage form according to claim 22, which provides a W₅₀from about 7 to about 16 hours.